Resistance to Systemic Therapies in Clear Cell Renal Cell Carcinoma: Mechanisms and Management Strategies

Makhov, Petr; Joshi, Shreyas; Ghatalia, Pooja; Kutikov, Alexander; Uzzo, Robert G.; Kolenko, Vladimir

doi:10.1158/1535-7163.mct-17-1299

Cited by 373 publications

(316 citation statements)

References 117 publications

(144 reference statements)

Supporting

Mentioning

311

Contrasting

Unclassified

Order By: Relevance

“…N‐linked glycosylation is only one component of the complex glycan functions in normal and diseased kidneys that include many roles for O‐linked glycans, glycosaminoglycans, and glycolipids . Because of the critical need to improve outcomes for promising immunotherapy and angiogenesis targeted treatments for ccRCC that work in subsets of patients, continued evaluation of N‐linked glycosylation and other glycan classes in this context could provide new therapeutic and diagnostic assay leads.…”

Section: Resultsmentioning

confidence: 99%

“…Renal cell carcinoma derived from epithelial tubular cells represents 90% of kidney cancers, and clear‐cell renal cell carcinoma (ccRCC) is the most prevalent subtype comprising 70% to 80% of cases . Typically, ccRCC is detected at advanced stages and, in general, is highly resistant to standard chemotherapy and radiotherapy treatments leading to high rates of recurrence and mortality . The histopathological hallmark of ccRCC is a clear cytoplasm appearance, because of accumulation of multiple lipids and glycogen, associated with Warburg effect metabolism .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Defining the human kidney N‐glycome in normal and cancer tissues using MALDI imaging mass spectrometry

et al. 2020

View full text Add to dashboard Cite

Clear-cell renal cell carcinoma (ccRCC) presents challenges to clinical management because of late-stage detection, treatment resistance, and frequent disease recurrence. Metabolically, ccRCC has a well-described Warburg effect utilization of glucose, but how this affects complex carbohydrate synthesis and alterations to protein and cell surface glycosylation is poorly defined. Using an imaging mass spectrometry approach, N-glycosylation patterns and compositional differences were assessed between tumor and nontumor regions of formalin-fixed clinical ccRCC specimens and tissue microarrays. Regions of normal kidney tissue samples were also evaluated for N-linked glycan-based distinctions between cortex, medullar, glomeruli, and proximal tubule features. Most notable was the proximal tubule localized detection of abundant multiantennary N-glycans with bisecting N-acetylglucosamine and multziple fucose residues. These glycans are absent in ccRCC tissues, while multiple tumor-specific N-glycans were detected with tri-and tetra-antennary structures and varying levels of fucosylation and sialylation. A polycystic kidney disease tissue was also characterized for N-glycan composition, with specific nonfucosylated glycans detected in the cyst fluid regions. Complementary to the imaging mass spectrometry analyses was an assessment of transcriptomic gene array data focused on the fucosyltransferase gene family and other glycosyltransferase genes. The transcript levels of the FUT3 and FUT6 genes responsible for the enzymes that add fucose to N-glycan antennae were significantly decreased in all ccRCC tissues relative to matching nontumor tissues. These striking differences in glycosylation associated with ccRCC could lead to new mechanistic insight into the glycobiology underpinning kidney malignancies and suggest the potential for new therapeutic interventions and diagnostic markers. K E Y W O R D Sclear-cell renal cell carcinoma, fucosylation, MALDI imaging, N-glycosylation, polycystic kidney disease

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Defining the human kidney N‐glycome in normal and cancer tissues using MALDI imaging mass spectrometry

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Unpredictable response to treatment represents one of the most controversial issues in cc RCC. Resistance to therapy is based on an incomplete mechanism of action (21), and there is no effective definitive therapeutic tool available (22). Lichner et al recently reported that Sunitinib therapy for advanced RCC induces selection of a tumor cells subpopulation able to survive and to grow as spheroids in tumor models xenografts (23).…”

mentioning

confidence: 99%

Intracellular Chloride Ion Channel Protein-1 Expression in Clear Cell Renal Cell Carcinoma

Neşiu

Cîmpean

Ceauşu

et al. 2019

Cancer Genomics Proteomics

View full text Add to dashboard Cite

Background/Aim: Chloride intracellular channel 1 (CLIC1) represents a promising target for personalized therapy. Our aim was to assess CLIC1 expression in clear cell renal cell carcinoma (cc RCC) and identify its possible prognostic role. Materials and Methods: Fifty cases of cc RCC were evaluated and selected for immunohistochemistry. CLIC1 expression was correlated with tumor grade, invasion and heterogeneity. Results: A total of 87.5% of the cases were CLIC1 positive, with either a homogeneous (31.42%) or a heterogeneous (68.57%) pattern. Low, mild and strong CLIC1 expressing tumors were defined based on nuclear (N), cytoplasmic (C), membrane (M) or combinations of them (NC, NM, CM, NCM) in terms of CLIC1 distribution. A significant correlation was found between tumor grade and percent of positive tumor cells (p=0.017). For G3 tumors, CLIC1 cytoplasmic expression was strongly correlated with high expression status (p=0.025) and tumor heterogeneity (p=0.004). CLIC1 expression was also correlated with metastasis (p=0.046).

show abstract

“…This observation may be due to the special pathological type of PCCCL. Similarly, traditional chemo-and radio-therapy are largely ineffective in treating any renal cell carcinoma subtype, and the underlying mechanistic reasons need to be further explored [42].…”

Section: Discussionmentioning

confidence: 99%

Predictors and survival of Primary clear cell carcinoma of liver: a population-based study of an uncommon primary liver tumor

Wen¹,

Yao²,

Xue³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: The clinicopathological features and prognostic factors of primary clear cell carcinoma of the liver (PCCCL) remain unknown. Aims: We aimed to determine the clinical, pathological, demographic, and therapeutic characteristics of PCCCL and the effects of these factors on the prognosis. Methods: Patients were selected from the "Surveillance, Epidemiology and End Results" (SEER) database. Data were analyzed with the Kaplan-Meier, Cox proportional hazards regression, and multivariate ordinal regression analyses. Results: We included 248 PCCCL patients with an average age of 64.1 years. The majority (50.4%) had low pathological grade (grade I/II). The 3-, 5-, and 10-year overall survival (OS) probabilities and disease-specific survival (DSS) rates were 33.8%, 23.2%, 12.2%, and 39.8%, 28.3%, 19.1%, respectively. The widowed patients (OS, P=0.271; DSS, P=0.022) with tumor ≥ 1 cm (OS, P=0.001; DSS, P=0.002) had a higher risk of death. Uninsurance and medicaid were independently associated with a shorter survival (OS, P=0.029; DSS, P=0.017). Among surgical means, total proctectomy along with total colectomy, and wedge or segmental resection/partial proctosigmoidectomy were more beneficial to PCCCL. The black PCCCL patients had a poorer survival than the white group. Furthermore, pathological grade I PCCCL was more likely to present AJCC stage I (P=0.005, OR=-1.062). Conclusion: PCCCL patients had a poor outcome. PCCCL was inclined to be localized, male-prevalent and lower pathological grade. Insurance, tumor size, and marital status were independent prognostic factors for OS and DSS, whereas race affected only OS. Surgery could improve OS and DSS. Moreover, highly differentiated PCCCL was susceptible to early AJCC stage.

show abstract

Resistance to Systemic Therapies in Clear Cell Renal Cell Carcinoma: Mechanisms and Management Strategies

Cited by 373 publications

References 117 publications

Defining the human kidney N‐glycome in normal and cancer tissues using MALDI imaging mass spectrometry

Defining the human kidney N‐glycome in normal and cancer tissues using MALDI imaging mass spectrometry

Intracellular Chloride Ion Channel Protein-1 Expression in Clear Cell Renal Cell Carcinoma

Predictors and survival of Primary clear cell carcinoma of liver: a population-based study of an uncommon primary liver tumor

Contact Info

Product

Resources

About